The overall goals of this project are to develop effective medications to treat cocaine addiction while concurrently investigating the biological basis for individual primate responses to candidate medications. The dopamine transporter, a principal target of cocaine, and transport inhibitors are the central focus of the research. With molecular, biochemical, behavioral and brain imaging techniques, we will assess the therapeutic potential of dopamine transport inhibitors. The research is based on exciting leads generated over the previous project period that evolved into four aims: 1. In pursuit of a cocaine antagonist, we developed a "tropane horse", designed to react covalently with the dopamine transporter (DAT), block cocaine access to the transporter but spare dopamine transport. We will investigate this class of compounds and cocaine replacements in vitro and in behavioral paradigms to identify promising, leads. 2. In support of this goal, we will conduct PET imaging procedures to identify effective cocaine replacements and antagonists. PET imaging of the DAT with [11C]altropane will identify compounds that fully occupy the dopamine transporter (cocaine replacements) and others that block cocaine access to the DAT but do not modify extracellular dopamine levels (cocaine antagonist). 3. Monkeys display strikingly different responses to dopamine transport inhibitors that are inversely correlated with baseline levels of activity. PET imaging of the dopamine transporter and gencityping of the dopamine transporter gene will clarify the association between transporter density, activity levels, and polymorphisms in the dopamine transporter gene. 4. As pre-synaptic neuroadaption elicited by cocaine may contribute to the addictive process, the effects of chronic administration of select candidate medications on transporter density and dopamine release will be monitored by PET imaging and in post-mortem tissue. This integrated research pro-ram will further the development of candidate medications to treat cocaine addiction and provide fundamental information on the neurobiological mechanisms underlying the behavioral effects of psychostimulants.